Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, irreversible memory loss, disorientation, and language impairment. Alzheimer's disease (AD) is a common neurodegenerative disease of the brain. It is a significant medical problem with a high prevalence in millions of elder people. Major neuropathology observations of postmortem AD brains depict the presence of senile plaques (containing β-amyloid (Aβ) aggregates) and neurofibrillary tangles (highly phosphorylated tau proteins). Currently, there is no definitive imaging method to diagnose AD, except by postmortem biopsy and staining of the brain tissue which demonstrates the senile plaques containing predominantly Aβ aggregates.
Several genomic factors have been linked to AD. Familial AD (or early onset AD) has been reported to have mutations in genes encoding β-amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) (Berezovska, O, A Lleo, L D Herl, et al. “Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein.” J Neurosci 25:3009 (2005); Deng, Y, L Tarassishin, V Kallhoff, et al. “Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.” J Neurosci 26:3845 (2006); Hardy, J, D J Selkoe “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.” Science 297:353 (2002); Selkoe, D J “Alzheimer's disease: genes, proteins, and therapy.” Physiol Rev 81:741 (2001)). The exact mechanisms of these mutations which lead to the development of AD are not fully understood; however, the formation of Aβ plaques in the brain is a pivotal event in the pathology of Alzheimer's disease.
Amyloidosis is a condition characterized by the accumulation of various insoluble, fibrillar proteins in the tissues of a patient. An amyloid deposit is formed by the aggregation of amyloid proteins, followed by the further combination of aggregates and/or amyloid proteins. Formation of soluble and diffusible Aβ and Aβ aggregates in the brain are now considered the critical events, which produce various toxic effects in neuronal cells leading to the formation of neuritic plaques (Catalano, S M, E C Dodson, D A Henze, et al. “The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimer's Disease.” Curr Top Med Chem 6:597 (2006); Hardy, (2002); Jicha, G A, J E Parisi, D W Dickson, et al. “Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia.” Arch Neurol 63:674 (2006); Rosenberg, R N “Explaining the cause of the amyloid burden in Alzheimer disease.” Arch Neurol 59:1367 (2002); Thal, D R, E Capetillo-Zarate, K Del Tredici, et al. “The development of amyloid beta protein deposits in the aged brain.” Sci Aging Knowledge Environ 2006:re1, (2006)). Recent reports have suggested that β-amyloid aggregates, i.e. Aβ plaques, in the brain play a key role in a cascade of events leading to AD. Postmortem examination of AD brain sections reveals abundant senile plaques (SPs) composed of amyloid-β (Aβ) peptides and numerous neurofibrillary tangles (NFTs) formed by filaments of highly phosphorylated tau proteins (for recent reviews and additional citations see Ginsberg, S. D., et al., “Molecular Pathology of Alzheimer's Disease and Related Disorders,” in Cerebral Cortex: Neurodegenerative and Age-related Changes in Structure and Function of Cerebral Cortex, Kluwer Academic/Plenum, NY (1999), pp. 603-654; Vogelsberg-Ragaglia, V., et al., “Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer's Disease,” Alzheimer's Disease, Lippincot, Williams & Wilkins, Philadelphia, Pa. (1999), pp. 359-372).
While the exact mechanisms underlying AD are not fully understood, all pathogenic familial AD (FAD) mutations studied thus far increase production of the more amyloidogenic 42-43 amino-acid long form of the Aβ peptide. Thus, at least in FAD, dysregulation of Aβ production appears to be sufficient to induce a cascade of events leading to neurodegeneration. Indeed, the amyloid cascade hypothesis suggests that formation of extracellular fibrillar Aβ aggregates in the brain may be a pivotal event in AD pathogenesis (Selkoe, D. J., “Biology of β-amyloid Precursor Protein and the Mechanism of Alzheimer's Disease,” Alzheimer's Disease, Lippincot Williams & Wilkins, Philadelphia, Pa. (1999), pp. 293-310; Selkoe, D. J., J. Am. Med. Assoc. 283:1615-1617 (2000); Naslund, J., et al., J. Am. Med. Assoc. 283:1571-1577, (2000); Golde, T. E., et al., Biochimica et Biophysica Acta 1502:172-187 (2000)).
Significant circumstantial evidence suggests that fibrillary Aβ plaques consisting predominately of aggregates of Aβ40 and Aβ42 peptides play a major role in AD pathogenesis —“Amyloid Cascade Hypothesis” (Armstrong, R A “Plaques and tangles and the pathogenesis of Alzheimer's disease.” Folia Neuropathol 44:1 (2006); Golde, T E “The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease.” Brain Pathol 15:84 (2005); Hardy, J “Has the amyloid cascade hypothesis for Alzheimer's disease been proved?” Curr Alzheimer Res 3:71 (2006); Hardy (2002); Marchesi, V T “An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease.” Proc Natl Acad Sci USA 102:9093 (2005)). ApoE4 expression appears to increase the risk of AD (Fryer, J D, J W Taylor, R B DeMattos, et al. “Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.” J Neurosci 23:7889 (2003)). It is likely that amyloid precursor protein (APP) is degraded by several proteases, among which the catabolism reactions of β- and β-secretases on APP lead to the production of excess Aβ. The excessive burden of Aβ, produced by various normal or abnormal mechanisms, may represent the starting point of neurodegenerative events. The fibrillar aggregates of amyloid peptides, Aβ40 and Aβ42, are major metabolic peptides derived from amyloid precursor protein found in senile plaques and cerebrovascular amyloid deposits in AD patients (Xia, W., et al., J. Proc. Natl. Acad. Sci. U.S.A. 97:9299-9304, (2000)). Prevention and reversal of Aβ plaque formation are being targeted as a treatment for this disease (Selkoe, D., J. JAMA 283:1615-1617 (2000); Wolfe, M. S., et al., J. Med. Chem. 41:6-9, 1998; Skovronsky, D. M., and Lee, V. M., Trends Pharmacol. Sci. 21:161-163 (2000)).
Early appraisal of clinical symptoms for diagnosis of AD is often difficult and unreliable (Boss, M A “Diagnostic approaches to Alzheimer's disease.” Biochim Biophys Acta 1502:188 (2000)). Positron emission tomography (PET) and single photon emission tomography (SPECT) imaging of regional cerebral blood flow (rCBF) for diagnosis and monitoring of patients with AD have been reported (Ishii, K, S Minoshima “PET is better than perfusion SPECT for early diagnosis of Alzheimer's disease—for.” Eur J Nucl Med Mol Imaging 32:1463 (2005); Mega, M S, I D Dinov, L Lee, et al. “Orbital and dorsolateral frontal perfusion defect associated with behavioral response to cholinesterase inhibitor therapy in Alzheimer's disease.” J Neuropsychiatry Clin Neurosci 12:209 (2000a); Mega, M S, L Lee, I D Dinov, et al. “Cerebral correlates of psychotic symptoms in Alzheimer's disease.” J Neurol Neurosurg Psychiatry 69:167 (2000b); Tang, B N, S Minoshima, J George, et al. “Diagnosis of suspected Alzheimer's disease is improved by automated analysis of regional cerebral blood flow.” Eur J Nucl Med Mol Imaging 31:1487 (2004)). Diagnosis of AD based on regional glucose metabolism in the brain has been evaluated using PET imaging with [18F]2-fluoro-2-deoxyglucose (FDG). The overall performance of FDG/PET is favorable for routine clinical evaluation of suspected AD (Frey, K A, S Minoshima, D E Kuhl “Neurochemical imaging of Alzheimer's disease and other degenerative Dementias.” Q J Nucl Med 42:166 (1998); Hoffman, J M, K A Welsh-Bohmer, M Hanson, et al. “FDG PET imaging in patients with pathologically verified dementia.” J Nucl Med 41:1920 (2000); Minoshima, S “Imaging Alzheimer's disease: clinical applications.” Neuroimaging Clin N Am 13:769 (2003); Minoshima, S, B Giordani, S Berent, et al. “Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease.” Ann Neurol 42:85 (1997); Phelps, M E “PET: the merging of biology and imaging into molecular imaging.” J Nucl Med 41:661 (2000); Silverman, D H S, M E Phelps “Invited Commentary: Evaluating Dementia Using PET: How Do We Put into Clinical Perspective What We Know to Date?” J Nucl Med 41:1929 (2000)). While imaging rCBF and glucose metabolism may have some use in AD patients, none of these modalities provide any information on the presence or quantity of Aβ aggregates in the brain.
Various approaches in trying to inhibit the production and reduce the accumulation of fibrillar Aβ in the brain are currently being evaluated as potential therapies for AD (Skovronsky, D. M. and Lee, V. M., Trends Pharmacol. Sci. 21:161-163 (2000); Vassar, R., et al., Science 286:735-741, 1999; Wolfe, M. S., et al., J. Med. Chem. 41:6-9, 1998; Moore, C. L., et al., J. Med. Chem. 43:3434-3442 (2000); Findeis, M. A., Biochimica et Biophysica Acta 1502:76-84, 2000; Kuner, P., Bohrmann, et al., J. Biol. Chem. 275:1673-1678 (2000)). It is therefore of interest to develop ligands that specifically bind fibrillar Aβ aggregates. Since extracellular SPs are accessible targets, these new ligands could be used as in vivo diagnostic tools and as probes to visualize the progressive deposition of Aβ in studies of AD amyloidogenesis in living patients. Development of Aβ plaque-specific imaging agents has been reported previously (for review see Blennow, K, H Zetterberg “Pinpointing plaques with PIB.” Nat Med 12:753 (2006b); Huddleston, D E, S A Small “Technology Insight: imaging amyloid plaques in the living brain with positron emission tomography and MRI.” Nat Clin Pract Neurol 1:96 (2005); Mathis, C A, Y Wang, W E Klunk “Imaging b-amyloid plaques and neurofibrillary tangles in the aging human brain.” Curr Pharm Des 10:1469 (2004); Nichols, L, VW Pike, L Cai, et al. “Imaging and in vivo quantitation of beta-amyloid: an exemplary biomarker for Alzheimer's disease?” Biol Psychiatry 59:940 (2006); Schmidt, B, HA Braun, R Narlawar “Drug development and PET-diagnostics for Alzheimer's disease.” Curr Med Chem 12:1677 (2005)).
Potential ligands for detecting Aβ aggregates in the living brain must cross the intact blood-brain barrier. Thus brain uptake can be improved by using ligands with relatively smaller molecular size and increased lipophilicity. Highly conjugated thioflavins (S and T) are commonly used as dyes for staining the Aβ aggregates in the AD brain (Elhaddaoui, A., et al., Biospectroscopy 1:351-356 (1995)). To this end, several interesting approaches for developing fibrillar Aβ aggregate-specific ligands have been reported (Ashburn, T. T., et al., Chem. Biol. 3:351-358 (1996); Han, G., et al., J. Am. Chem. Soc. 118:4506-4507 (1996); Klunk, W. E., et al., Biol. Psychiatry 35:627 (1994); Klunk, W. E., et al., Neurobiol. Aging 16:541-548 (1995); Klunk, W. E., et al., Society for Neuroscience Abstract 23:1638 (1997); Mathis, C. A., et al., Proc. XIIth Intl. Symp. Radiopharm. Chem., Uppsala, Sweden:94-95 (1997); Lorenzo, A. and Yankner, B. A., Proc. Natl. Acad. Sci. U.S.A. 91:12243-12247 (1994); Zhen, W., et al., J. Med. Chem. 42:2805-2815 (1999); Klunk, W. E., et al., J. Histochem. Cytochem. 37:1273-1281 (1989)).
The approach has been based on highly conjugated dyes, such as Congo Red and Chrysamine G (CG) (Dezutter, N A, R J Dom, T J de Groot, et al. “99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease.” Eur J Nucl Med 26:1392 (1999); Klunk, W E, M L Debnath, A M Koros, et al. “Chrysamine-G, a lipophilic analogue of Congo red, inhibits Aβ-induced toxicity in PC12 cells.” Life Sci 63:1807 (1998); Klunk, W E, M L Debnath, J W Pettegrew “Small-molecule beta-amyloid probes which distinguish homogenates of Alzheimer's and control brains.” Biol Psychiatry 35:627 (1994)). Thioflavin S and T have also been used in fluorescent staining of plaques and tangles in postmortem AD brain sections (Elhaddaoui, A, E Pigorsch, A Delacourte, et al. “Competition of congo red and thioflavin S binding to amyloid sites in Alzheimer's diseased tissue.” Biospectroscopy 1:351 (1995)). More abbreviated forms of Chrysamine G (CG), such as styrylbenzenes, have been reported as fluorescent dyes for staining amyloid aggregates (Link, C D, C J Johnson, V Fonte, et al. “Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34.” Neurobiol Aging 22:217 (2001); Styren, S D, R L Hamilton, G C Styren, et al. “X-34, a fluorescent derivative of Congo Red: a novel histochemical stain for Alzheimer's disease pathology.” J Histochem Cytochem 48:1223 (2000)). They are useful research tools but these charged and bulky agents do not cross intact blood-brain barrier.
A highly lipophilic tracer, [18F]FDDNP, for binding both tangles (mainly composed of hyperphosphorylated tau protein) and plaques (containing Aβ protein aggregates) has been reported. (Shoghi-Jadid K, et al., Am J Geriatr Psychiatry. 10:24-35 (2002); Barrio, J R, S- C Huang, G Cole, et al. “PET imaging of tangles and plaques in Alzheimer's disease with a highly hydrophobic probe.” J Lab Compds Radiopharm 42 Suppl. 1:S194, (1999a); Barrio, J R, S C Huang, G M Cole, et al. “PET imaging of tangles and plaques in Alzheimer's disease.” J Nucl Med 40:70P, (1999b)). Preliminary studies in humans suggested that [18F]FDDNP showed a higher retention in regions of brain suspected of having tangles and plaques (Kepe, V, J R Barrio, S C Huang, et al. “Serotonin 1A receptors in the living brain of Alzheimer's disease patients.” Proc Natl Acad Sci USA 103:702 (2006); Shoghi-Jadid, K, J R Barrio, V Kepe, et al. “Exploring a mathematical model for the kinetics of beta-amyloid molecular imaging probes through a critical analysis of plaque pathology.” Mol Imaging Biol 8:151 (2006); Shoghi-Jadid, K, J R Barrio, V Kepe, et al. “Imaging beta-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization.” Nucl Med Biol 32:337 (2005); Shoghi-Jadid, K, G W Small, E D Agdeppa, et al. “Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease: Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer disease.” Am J Geriatr Psychiatry 10:24, (2002)). Using positron-emission tomography (PET), it was reported that this tracer specifically labeled deposits of plaques and tangles in nine AD patients and seven comparison subjects. (Nordberg A. Lancet Neurol. 3:519-27 (2004)). Using a novel pharmacokinetic analysis procedure called the relative residence time of the brain region of interest versus the pons, differences between AD patients and comparison subjects were demonstrated. The relative residence time was significantly higher in AD patients. This is further complicated by an intriguing finding that FDDNP competes with some NSAIDs for binding to Aβ fibrils in vitro and to Aβ plaques ex vivo (Agdeppa E D, et al. 2001; Agdeppa E D, et al., Neuroscience. 2003; 117:723-30).
A neutral and lipophilic thioflavin derivative, [11C]6-OH-BTA-1 (PIB), showed excellent brain penetration and initial brain uptake, and displayed a high binding affinity to Aβ plaques (Ki=2.8 nM) (Klunk, W E, Y Wang, G- f Huang, et al. “Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain.” Life Sci 69:1471 (2001); Mathis, C A, B J Bacskai, STBMC Kajdasz, et al. “A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain.” Bioorg Med Chem Lett 12:295 (2002a); Mathis, C A, Y Wang, W E Klunk “Imaging b-amyloid plaques and neurofibrillary tangles in the aging human brain.” Curr Pharm Des 10:1469 (2004); (Mathis C A, et al., Curr Pharm Des. 10:1469-92 (2004); Mathis C A, et al., Arch. Neurol. 62:196-200 (2005)). Contrary to that observed for [18F]FDDNP, [11C]6-OH-BTA-1 binds specifically to fibrillar Aβ in vivo. Patients with diagnosed mild AD showed marked retention of [11C]6-OH-BTA-1 in the cortex, known to contain large amounts of amyloid deposits in AD. In the AD patient group, [11C6]-OH-BTA-1 retention was increased most prominently in the frontal cortex. Large increases also were observed in parietal, temporal, and occipital cortices and in the striatum. [11C]6-OH-BTA-1 retention was equivalent in AD patients and comparison subjects in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Fluorinated PIB and related neutral thioflavin derivatives, such as BTA-1, have also been reported (Mathis, C A, D P Holt, Y Wang, et al. “18F-labeled thioflavin-T analogs for amyloid assessment.” J Nucl Med 43:166P, (2002b)).
In the past few years, successful PET imaging studies in AD patients with [11C]PIB has been reported (Klunk, W E, B J Lopresti, M D Ikonomovic, et al. “Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain.” J Neurosci 25:10598, (2005); Lopresti, B J, W E Klunk, C A Mathis, et al. “Simplified Quantification of Pittsburgh Compound B Amyloid Imaging PET Studies: A Comparative Analysis.” J Nucl Med 46:1959 (2005); Mathis, C A, W E Klunk, J C Price, et al. “Imaging technology for neurodegenerative diseases: progress toward detection of specific pathologies.” Arch Neurol 62:196 (2005); Price, J C, W E Klunk, B J Lopresti, et al. “Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B.” J Cereb Blood Flow Metab 25:1528 (2005)). Recently, [11C]PIB has been used in testing a limited number of patients with mild cognitive impairment (MCI) (Buckner, R L, A Z Snyder, B J Shannon, et al. “Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.” J Neurosci 25:7709 (2005); Nordberg, A “PET imaging of amyloid in Alzheimer's disease.” Lancet Neurol 3:519 (2004); Price, J C, W E Klunk, B J Lopresti, et al. “Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B.” J Cereb Blood Flow Metab 25:1528, (2005)). Using PIB/PET to study the relationship between Aβ plaque burden and AD neurological measurements, the results seem to suggest that there are some MC1 cases that convert to AD, while those with lower PIB uptake in the cortex appear to have less propensity to convert to AD (Engler, H, A Forsberg, O Almkvist, et al. “Two-year follow-up of amyloid deposition in patients with Alzheimer's disease.” Brain (2006); Mintun, M A, G N Larossa, Y I Sheline, et al. “[11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.” Neurology 67:446 (2006); Price, J C, S K Ziolko, L A Weissfeld, et al. “[O-15] Water and PIB PET imaging in Alzheimer's disease and mild cognitive impairment.” J Nucl Med:75p (abstract) (2006); Rentz, D M, J A Becker, E Moran, et al. “Amyloid imaging in AD, MCI, and highly intelligent older adults with Pittsburgh Compound-B (PIB).” J Nucl Med:289p (abstract) (2006); Villemagne, V L, S Ng, S J Gong, et al. “11C-PIB PET imaging in the differential diagnosis of dementia.” J Nucl Med:74p (abstract), (2006)).
Recently, another 11C labeled Aβ plaque-targeting probe, a stilbene derivative, [11C]SB-13, has been studied. In vitro binding using the [3H]SB-13 suggests that the compound showed excellent binding affinity and binding can be clearly measured in the cortical gray matter, but not in the white matter of AD cases. (Kung M-P, et al., Brain Res. 1025:98-105 (2004). There was a very low specific binding in cortical tissue homogenates of control brains. The Kd values of [3H]SB-13 in AD cortical homogenates were 2.4±0.2 nM. High binding capacity and comparable values were observed (14-45 pmol/mg protein) (Id.). As expected, in AD patients [11C]SB-13 displayed a high accumulation in the frontal cortex (presumably an area containing a high density of Aβplaques) in mild to moderate AD patients, but not in age-matched control subjects. (Verhoeff N P, et al., Am J Geriatr Psychiatry. 12:584-95, (2004)).
Recently, there have been reports on using an in vivo multiphoton optical imaging technique for invasive imaging of senile plaques in transgenic mice (by opening the skull) (Bacskai, B J, S T Kajdasz, R H Christie, et al. “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy.” Nat Med 7:369, (2001)). Additional improvements on developing near-infrared optical imaging agents have been reported (Bacskai, B J, G A Hickey, J Skoch, et al. “Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice.” Proc Natl Acad Sci USA 100:12462 (2003); Hintersteiner, M, A Enz, P Frey, et al. “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe.” Nat Biotechnol 23:577 (2005); Nesterov, E E, J Skoch, B T Hyman, et al. “In vivo optical imaging of amyloid aggregates in brain: design of fluorescent markers.” Angew Chem Int Ed Engl 44:5452 (2005)).
There are several potential benefits of imaging Aβ aggregates in the brain. The imaging technique will improve diagnosis by identifying potential patients with excess Aβ plaques in the brain; therefore, they may be likely to develop Alzheimer's disease. It will also be useful to monitor the progression of the disease. When anti-plaque drug treatments become available, imaging Aβ plaques in the brain may provide an essential tool for monitoring treatment. Thus, a simple, noninvasive method for detecting and quantitating amyloid deposits in a patient has been eagerly sought. Presently, detection of amyloid deposits involves histological analysis of biopsy or autopsy materials. Both methods have drawbacks. For example, an autopsy can only be used for a postmortem diagnosis.
In addition to the role of amyloid deposits in Alzheimer's disease, the presence of amyloid deposits has been shown in diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, β2-microglobulin amyloid in dialysis patients, inclusion body myositis, β2-amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type II insulinoma.
The direct imaging of amyloid deposits in vivo is difficult, as the deposits have many of the same physical properties (e.g., density and water content) as normal tissues. Attempts to image amyloid deposits using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules have provided some selectivity on the periphery of tissues, but have provided for poor imaging of tissue interiors.
It would be useful to have a noninvasive technique for imaging and quantitating amyloid deposits in a patient. In addition, it would be useful to have compounds that inhibit the aggregation of amyloid proteins to form amyloid deposits and a method for determining a compound's ability to inhibit amyloid protein aggregation.